Local heat, systemic hyperthermia and fever therapy have been empirically used as effective treatments for malignant, infectious and other diseases since antiquity. Therapeutic hyperthermia was first documented in the Edwin Smith surgical papyrus in the 17th century B.C. Coley's toxin extracts of Streptococcus erysipelatis (group A streptococcus) and Bacillus prodigiosus (Serratia marcescens) were used to induce fever for the treatment of patients with advanced cancer. The Nobel Prize was awarded for using fever therapy in the treatment of neurosyphilis with the injection of malarial blood. As late as 1955, the Mayo Clinic advocated using malariotherapy or heat therapy for cases of tertiary syphilis “resistant to penicillin”. Long term remissions in patients with inoperable carcinomas that were treated with hot baths and local heat applications have also been reported. Published observations on the disappearance of malignancies such as a soft tissue sarcoma in a patient experiencing high fever due to erysipelas and tumor lysis of Burkitt's lymphomas following malignant hyperthermia during surgical anesthesia are known. A comprehensive historical review on anecdotal observations and intuitive rational for the empirical use of therapeutic hyperthermia has been published by Myer, J. L.
The temperature of a body can be intentionally increased either by pyrogens to produce fever (fever therapy) or, by the induction of hyperthermia (therapeutic hyperthermia). Fever raises body temperature by elevating the thermoregulatory “set point” located in the preoptic region of the anterior hypothalamus. In so doing, the body physiologically works to maintain the higher temperature setting. The elevated core body temperature increased by fever may or may not be raised above the higher set point value. In contrast, induced hyperthermia always raises the body temperature above the hypothalamic thermoregulatory set point and the physiologically intact body attempts to lower it's core temperature back to the set point baseline.
Renewed clinical interest in hyperthermia has occurred over the past 35 years due to continued failure of standard therapies to treat various forms of cancer and emerging infections. Except for a few exceedingly rare forms of cancer like childhood leukemias and testicular cancer or immune responsive infections, chemotherapy, radiation or drug therapy often do very little except briefly extend survival. One of the major obstacles to “cure” disseminated cancer and infections has been the innate or acquired resistance of tumor cells and emerging microbes to antibiotics, drugs and treatments given in tolerable doses. Escalation of treatments, or use of multiple drugs to overcome resistance is invariably prevented by concomitant toxicities or development of multi-drug resistance. Further, in contrast to drugs, which represent a single molecular species that biochemically interact with specific enzymes or receptors of viruses, prokaryotes and eukaryotes, the action of hyperthermia is biophysical and global. Hyperthermia has no specific heat receptors. Therefore, the possibility of a point mutation causing a functional change in a receptor and conferring resistance to hyperthermia is unlikely, and would be equivalent to the development of resistance to the in vitro process of Pasteurization. Among pathogenic bacteria, it has been reported that only one variant in 1×106 cells of an original population is resistant to hyperthermia.
Hyperthermia has been used alone or in conjunction with radiation and chemotherapy in the treatment of a variety of malignancies. Overgaard et al., reported that a combination of heat and radiation results in complete control of twice as many melanoma lesions compared to radiation alone. Maeda, M., Watanabe, N. et al., published in Gastroenterologia Japonica, that hyperthermia with tumor necrosis factor resulted in successful treatment of hepatocellular carcinoma. Prospective randomized studies of hyperthermia combined with chemoradiotherapy for esophageal carcinoma demonstrated the cumulative three year survival rates to be more than doubled with the addition of hyperthermia to chemoradiotherapy. Combination chemotherapy with hyperthermia in metastatic breast cancer refractory to common therapies, i.e., failed prior hormonal therapy and chemotherapy, resulted in 39% complete remissions and 23% partial remissions: relief of bone pain was striking. Fujimoto, S., Takahashi, M. et al., demonstrated that the 5 year survival rate of patients with peritoneal carcinomatosis from gastric carcinoma treated with intraperitoneal hyperthermic chemoperfusion was 41.6%, whereas the 50% survival duration of the group that did not receive intraperitoneal hyperthermia was 110 days. Preoperative hyperthermia with chemotherapy and radiation is also known to improve long-term results in patients with carcinoma of the rectum, especially those with advanced disease. It is clinically known that regional, i.e., limb, hyperthermic perfusions with chemotherapy is useful for the treatment of melanoma. Combination therapy with hyperthermia and radiation has been successful in the treatment of non-Hodgkins lymphomas. More recently, a survival benefit of hyperthermia was shown in a prospective randomized trial for patients with glioblastoma multiforme undergoing radiotherapy. However, rigorous clinical prospective randomized trials with hyperthermia alone or, in combination with agents outside its use with radiation therapy have not been performed.
The scientific rationale for therapeutic hyperthermia in cancer therapy rests on known data from pre-clinical, in vitro and animal studies. Tumor cells in tissue culture have been demonstrated to be directly more sensitive to heat as compared to their non-malignant counterparts. Cells undergoing mitosis, synthesizing DNA in the ‘S-phase’, are especially more sensitive to hyperthermia. Human leukemic progenitor cells have been shown to be selectively killed by hyperthermia and, such in vitro use has been shown to purge bone marrow of residual tumor cells before autologous bone marrow transplantation. Microcalorimetric measurements confirm that tumorous tissues produce more heat and are “hotter” than their non-tumorous counterparts. As a consequence, they are less able to tolerate additional heat loads.
Tumor cells are also killed by heat indirectly. Tumor angiogenesis is inhibited by heat. Hyperthermia causes tumors to have increased heat retention with increased cytoxicity due to tumor neovasculature lacking smooth muscle and vessel wall precursors needed for cooling by vasodilation. Increased hypoxia, acidity, Fos gene death signaling, decreased nutrient supply and enhanced immunologic cytotoxicity have also been reported to be caused by hyperthermia and contribute to enhanced tumor cell death. Further, the combination of hyperthermia with chemotherapy and/or radiation has been shown to be supraadditive or synergistic on killing of tumors. Human gastric carcinoma cells have been shown to be selectively killed by a combination of cisplatin, tumor necrosis factor and hyperthermia: a 40% increase in cisplatin DNA damage was noted in the presence of the three agent combination over cisplatin alone or either dual combination. Numerous animal studies, including the initial publication by Crile, show that neoplasms transplanted into mice regress when treated with hyperthermia without irreparable damage to adjacent tissues.
Body temperature is a critical factor in determining host susceptibility, location of lesions, and the natural history of many infectious diseases. Temperature has direct effects on the growth of all microorganisms, including those that are pathogenic. Almost all of the bacteria that cause disease in humans grow optimally within the range of 33-41° C. and, their temperature growth characteristics are not easily altered in vitro. By example, the lesions of Hansen's disease (leprosy) caused by Mycobacterium leprae, characteristically grow and destroy the most acral, coolest parts of the body such as fingers, toes, external ear, the air-stream cooled nasal alae and larynx. Leprosy organisms proliferate and follow the coolest temperature gradients in the body, 25-33° C. In animals, the leprae organisms can only be grown in the armadillo or foot pads of mice where the in situ lesion temperatures are 27-30° C. Spontaneous improvement in leprosy lesions have been reported in patients following febrile illness. Fever therapy, hot baths and local heat therapy were formerly utilized in treating this disease. Hyperthermia is also known to destroy Treponema pallidum, the causative agent of syphilis, by heating five hours at 39° C., three hours at 40° C., two hours at 41° C. or one hour at 41.5° C. The spirochetes responsible for yaws, bejel, pinta and Lyme disease show similar temperature sensitivity.
Other bacteria that predominately cause lesions at cool sites and are susceptible to heat inactivation include, Neisseria gonorrhea, Hemophillus ducrei (chancroid), Mycobacterium ulcerans, Mycobacterium marinum (“swimming pool” granuloma), Diphtheria, etc. Further, hyperthermia has been reported to be synergistic with antibiotic and chemotherapy in the treatment of various bacterial diseases. Elevated body temperature potentiates the effect of penicillin on staphylococci and syphilis. Hyperthermia makes sulfadiazene bactericidal for streptococci. Moreover, recent controlled studies show that when antipyretics are used in animals with severe experimentally induced infections, there is increased mortality. Nonetheless, systemic hyperthermia has generally been abandoned as a treatment for bacterial infections with the advent of antibiotics.
Hyperthermia has remained an effective treatment for many fungal infections. Superficial dermatophytosis flourish in cooler regions of the body and heat treatment is oftentimes the only viable therapy for their chronic granulomatus lesions. By example, Sporothrix schenkii, the causative agent of sporotrichosis, has a temperature growth optimum well below 37° C. and is successfully eliminated by local hyperthermia. Similarly, patients with pseudallescheriosis unresponsive to antifungal antibiotics are healed with hyperthermic treatments. In Japan, pocket warmers, hot water and infrared heating remain current and effective treatments for various fungal infections. Systemic hyperthermia, utilizing a Liebel-Flarsheim (Kettering) Hypertherm Fever Cabinet, dramatically treated a case of disseminated sporotrichosis with recurrent iridocyclitis, repeated post-treatment cultures from the patient remained negative.
The role of hyperthermia in modulating the clinical course of other fungal infections, including histoplasmosis, North American blastomycosis, chromomycosis, cryptococcosis, paracoccidioidomycosis, Lobos' disease and candidiasis has been described. Fungi, such as Nocardia, Actinomyces and Aspergillus also proliferate in cooler regions of the body causing mandible (lumpy jaw) and foot lesions (Madura foot) respectively. In vitro heat sensitivity data for many of the above and other pathogenic fungi have been reported by Mackinnon et al., Silva and others.
The effect of temperature and hyperthermia on the pathogenesis of parasitic disease is also well known. Leishmaniasis, a wide spread parasitic disease transmitted by the bite of a sandfly, clinically infects 12 million people worldwide. The cutaneous and mucocutaneous lesions, i.e., Oriental sore, Baghdad boil, Delhi boil, Chiclero's ulcer and espundia, are often very destructive and permanently disfiguring. Hyperthermia with moist heat of 39° to 41° C. applied for 20 hours over several days has proven to be an effective treatment. In vitro, human macrophages infected with Leishmania mexicana are completely destroyed by heating at 39° C. for 3 days. All muco-cutaneous Leishmania strains, regardless of subspecies, demonstrate a growth optimum of 35° C. with only the L. tropica and L. donovani strains surviving temperatures of 39° C. Clinical observations have shown that hyperthermic treatment of one Leishmania lesion often invokes an immune response and results in the healing of other lesions over a 5-6 week period. The effect of hyperthermia on other parasites, including Trypanosoma cruzi, malaria, microfilaria, acanthamoeba, trematodes and cestodes has been published.
Increased body temperature is also recognized as a major factor in recovery from viral infections. Many viruses multiply better at temperatures below 37° C. and their multiplication is inhibited or stopped if the body temperatures exceeds 39° C. In vitro Rhinovirus replication, for example, falls off by 106 log units with an upward temperature shift of 2° C. (37° to 39° C.). Herpes virus replication, as well as the intracellular and extracellular herpes virus concentration, markedly decrease when the incubation temperature is elevated to 40° C. Varicella virus production in human fibroblastic cell culture is optimal at 37° C. and ceases at 39° C.
Beneficial effects of hyperthermia on the outcome of viral disease in laboratory animals infected with myxomatosis, encephalomyocarditis, herpes, gastroenteritis, rabies and the common cold in man have been documented. Influenza and viruses causing upper respiratory infections, such as the common cold, thrive in a cool body milieu of 30°-35° C. Temperature gradients in this range exist in the fall and winter within the oral, nasal, tracheal and laryngeal mucosa and lead to flu and influenza epidemics. Live respiratory-virus vaccines for influenza have been developed by use of heat-sensitive mutants that cannot reduplicate or cause clinical disease at 36°-37° C. It is known that even as little as a 0.5° C. difference in the ceiling replication temperature of a virus can have a dramatic effect on virulence and pathogenicity.
Other animal viruses such as Newcastle disease in chickens, rabbit papilloma, feline leukemia, rabbitpox, hoof-and-mouth disease in cattle, hand, foot, and mouth disease, human plantar warts, and the “grease” of horses, due to horsepox involvement of the colder acral extremities above the fetlocks, are known to be very sensitive to inhibition by heat. Heat treatment of cells infected with human immunodeficiency virus (HIV-1) at 39° C. for 2 days has been documented to significantly decrease viral production and reduce reverse transcriptase enzyme marker activity 30 fold. In vitro hyperthermia of 42.0° C. for 1 hour, 4 days apart selectively lowers HIV RNA loads in chronic (latent) infected T lymphocytes. Hyperthermia of 42° C. for 3 hours combined with tumor necrosis factor has been published to selectively kill all acute and chronically infected HIV cells in tissue culture.
Use of whole body hyperthermia has been reported to cause regression of Kaposis' sarcoma, clear oral candidiasis, eliminate hepatitis C, cause remission of Varicella-zoster, increase weight gain and improve CD4 lymphocytes counts in patients with acquired immunodeficiency syndrome (AIDS). Dramatic improvement with hyperthermia therapy has been documented in a patient infected with a debilitating Verruca vulgaris and HIV. The FDA has approved clinical trials involving hyperthermia for the treatment of AIDS with a patented extracorporeal blood heating machine to induce whole body hyperthermia. The FDA has recently expanded the extracorporeal heating machine trials to permit treatment of 40 HIV infected patients.
Hyperthermia can augment cytotoxicity and reverse drug resistance to many chemotherapeutic agents. Moreover, hyperthermia has also been shown to enhance the delivery of many novel cancer therapeutic agents, i.e., monoclonal antibodies to neoplasms with resultant improvement in antitumor effect; enhance the delivery of gene therapy with use of viral vectors; and, augment drug delivery and antitumor effects when using drug containing liposomes. In addition to increasing the rate of extravasation of liposomes from the vascular compartment by a factor of 40-50, hyperthermia can also be used to selectively release chemotherapeutic agents from liposomes designed to be thermosensitive. Thermosensitive liposomes are small vesicles composed of lipid phosphatidylcholine moieties constructed to contain and transport a variety of drugs. The liposomes are designed to remain stable in the blood and tissues at physiologic temperatures. When passing through an area of heated tissue however, they dissolve and effectively release their encapsulated contents. Thermosensitive liposomes are used to entrap and carry drugs whose systemic toxicity is desired to be limited to a particular heated tumor, organ or tissue. Examples of drugs that have been encapsulated into liposomes include methotrexate, doxorubicin, amphotericin B, cisplatin and others. Liposomes can be designed so as to release their contents at pre-determined temperatures.
Hyperthermia has also been an effective solution for the treatment of a variety of heat labile toxin or poisonous envenomations. For example, an easy treatment for Scorpaenidae and Siganidae envenomation is the local application of heat. The major poisonous component of this and many other venoms from lionfish, weever fish, bullrout, sculpin, surgeon fish, scorpion fish, stonefish, butterfly cod, etc., is a very heat labile, non-dialyzable protein. As opposed to the nuances of using specific anti-venom, immersing the envenomated area or patient in hot water, or applying other forms of hyperthermia, is a simple and prompt treatment.
Standard clinical methods of inducing hyperthermia are dependent on the deposition of exogenous heat to that normally produced by the metabolism. All current deliberate and controlled methods of heating require an external source of energy. Non-surgical methods of heating include: hot air, ultrasound, microwaves, paraffin wax baths, hot water blankets, radiant heat devices, high temperature hydrotherapy and combinations thereof. Invasive means of inducing hyperthermia include surgical insertion of various heating devices, infusion of heated solutions into the peritoneal cavity through catheters or heating the blood extracorporeally through a heat exchanger. The later method, developed by Parks et al., involves the surgical placement of a femoral arterio-venous shunt for the removal, heating and replacement of blood to induce whole body hyperthermia. A more recent experimental improvement on this method has been the induction of whole body hyperthermia with veno-venous shunt perfusions. Several machines have been patented for extracorporeal heating of blood to induce hyperthermia (see U.S. Pat. Nos. 5,391,142 and 5,674,190).
Endogenous heating by creating fevers induced with toxins, pyrogens and microorganisms have been used in the past and have recently been re-attempted. Heimlich has been reported to use Malaria therapy for the treatment of Lyme disease, AIDS and malignancy. Pontiggia et al, treated AIDS patients by combining fever, induced by parenteral injections of a streptococcal lysate preparations, with hyperthermia generated by an infrared heating bed.
Another way that the prior art has dealt with inducing hyperthermia has been by introducing micron size magnetic particles and subjecting them to either magnetic fields or hyperbaric oxygen (see U.S. Pat. No. 4,569,836). This method was designed for the treatment of cancer based on the belief that cancer cells would engulf the particles and concentrate them intracellularly. A magnetic field would then be applied to heat the particles and generate lethal hyperthermia within the cancer cells. A modification of this technology is the use of magnetic cationic liposomes to induce intracellular hyperthermia. This technology was based on the observation that glioma cells have a greater affinity for positively charged rather than ‘neutral’ magnetic liposomes. A more recent variation on this science has been developed in Germany using ‘targeted’ magnetoliposomes. This methodology has been developed in an attempt to treat AIDS by using magnetic nanoparticles coupled to either CD4 lymphocyte or anti-gp120 HIV antibodies. The magnetic nanoparticles are intended to selectively bind to either the HIV protein envelope or the HIV infected cells and then be heated by external high-frequency alternating magnetic fields.
Whether invasive or non-invasive, all current methods of inducing hyperthermia depend on an external energy source and cannot safely deliver adequate power to result in therapeutic heating. Delivery of heat to obtain the actual desired temperature to deep target tissues has not been possible because of the actual physics involved in the thermodynamic, conductive transfer of heat from the outside into the cell. Heating tissues deeper than five centimeters below the skin with microwave, radio frequency or ultrasound devices is difficult because energy absorption is not uniform or focused. Radiant heat, hot water, molten wax and other methods cause excessive heating of subcutaneous fat which acts as a barrier to body heat gain. Common adverse effects of such external heating methods include surface skin burns, blistering, ulcerations, secondary opportunistic infections and pain. Additionally, many tumors have high blood flow cooling which nullifies any potential therapeutic gain achievable through the use of such extracellular, systemic hyperthermia devices. Also, insufficient heating power prolongs the induction time required to reach the actual therapeutic temperature. This promotes resistance to heat treatment through the development of the heat shock response and thermotolerance.
High frequency electromagnetic devices used to heat intracellular magnetic particles invariably induce eddy currents within the body making it difficult to provide uniform, controlled and safe heating without toxic effects to normal cells. Further, not all tumors possess characteristics that cause them to selectively take up magnetic particles or have an affinity for positively charged magnetic liposomes. Also, magnetic cationic liposome particles are subject to various neutralizing interactions with anions, giving them a short charged half-life. Moreover, the complexity of using specific anti-HIV antibodies bound to electromagnetic particles also assumes a non-mutating HIV genome with stable antigenic determinants. To the contrary, a high mutation rate in the HIV genome and it's protein antigenic determinants is known to exist and is the main obstacle to the development of an effective vaccine. Such treatments therefore, do not selectively heat transformed cells without heating and injuring normal cells.
Extracorporeal blood heating methods require surgery and anesthesia. Further, as with all external heating methods, temperature variances and toxic conductive thermogradients from the point of initial heating to the target tissue cannot be avoided. By example, bone marrow temperatures are consistently known to be 1°-2° C. below the average body core temperature achieved by extracorporeal blood hyperthermia. This is a major problem in systemic hyperthermic therapy since the marrow is a common repository of metastatic cancer cells and infectious microorganisms. Therapeutic bone marrow temperatures are not achievable due to the fact that the intermediate tissues between the blood and the marrow create a temperature gradient cooling the blood before it reaches the bone marrow. Since efficacy and toxicity of hyperthermia depend on both the actual temperature and duration of heating, delivering the desired temperature-and-duration of heating (thermal dose) to the bone marrow would require the blood and intermediate tissues to be heated beyond that which is safe for normal, healthy cells. A multicentre European trial documented that only 14% of all protocols achieve required target temperatures. Further, current extracorporeal heating methodology and equipment is labor intensive, time-consuming and expensive.
Use of fever inducing agents such as live microorganisms, pyrogens and toxin lysates is clinically uncontrollable, unpredictable or insufficient as to both the degree and duration of temperature increase.
Further reasons why hyperthermia has not yet become more widely accepted as a mode of therapy is because current heating machines are not compatible with noninvasive temperature measurement technology. Measurement of the actual temperatures reached in target tissues is critical for heating efficacy, i.e., determining the thermal dose. Recently, noninvasive thermometry with Magnetic Resonance Imaging (MRI), ultrasound backscatter, electrical impedance, electromagnetic adaptive feedback and advanced, high-precision pixel infrared temperature imaging have been developed. To use MRI or other equipment to monitor real time hyperthermia however, it is necessary to combine a hyperthermia device with an MRI unit. This has proven to be difficult and costly since each device is functionally disturbed, if not damaged, by the presence of the other.
The exact molecular and cellular mechanism by which heat kills or inactivates tumor cells and microorganisms is unknown. Heat is an entropic agent and acts globally on every molecule constituting the cell. Heating is known to cause conformational changes in proteins, denature enzymes and affect cell membrane fluidity. By example, herpes simplex virus (type 1) thymidine kinase has a shortened half-life at 40° C. of only 30 minutes. The transforming gene product-enzyme of Rous sarcoma virus (protein phosphatase), a critical protein for cellular regulation, is totally inactivated in 30 minutes at 41° C. Hyperthermia is known to increase the formation of oxygen free radicals, including superoxide, hydroxyl, hydroperoxyl, hydrogen peroxide and lipid peroxides. These reactive oxygen species react indiscriminately and oxidize many organic molecules causing DNA damage, protein denaturation, lipid peroxidation and other destructive chain reactions. Acid microenvironments, known to exist in tumors and microorganisms with high rates of glycolysis (Embden-Meyerhof Pathway) and lactic acid production, favor protonation of the superoxide radical to form the highly reactive and toxic hydroperoxyl radical. Thus, thermal sensitivity of many tumors increases with decreasing intracellular pH. As compared to normal cells, many malignant and virally transformed cells have a reduced total functional capacity to withstand the increase flux of oxygen free radicals produced by hyperthermia.
On the intracellular level, moderate heating is known to activate phospholipase A2, which increases the formation of pro-inflammatory mediators such as the leukotrienes, prostaglandins and eicosanoids. Heat also increases release of intracellular calcium through the stimulation of phospholipase C. Calcium cycling across the mitochondrial membrane appears critical to the increased production of oxygen free radicals. Increased intracellular calcium also inhibits the mitochondrial, anti-apoptotic Bcl-2 protein and induces the production of heat shock proteins, mediating thermotolerance. Heat injury to the intracellular tubulin network, lysosomes, Golgi bodies, mitochondria, and control of RNA splicing are some of the many known subcellular systems affected by heat. While the initial primary event leading to cell death by hyperthermia is unknown, a decrease in mitochondrial membrane potential followed by uncoupling of oxidative phosphorylation and generation of reactive oxygen species on the uncoupled respiratory chain are the first biochemical alterations detectable in cells irreversibly committed to apoptosis. The cytotoxic effect of hyperthermia is thus believed to be caused by numerous changes and complex damage to multiple vital cell functions. Those biochemicals altered by heat and essential to the function or viability of the cell are the pivotal targets of therapeutic heating.
The mode of hyperthermic cell injury is dependent on the severity of the heat stress, temperature and duration of heating. Moderate heating of 39°-42° C. is used therapeutically and is known to promote programmed cell death through apoptosis, an active process of selectively eliminating heat sensitive cells without inflammation, bystander-cell death or subsequent tissue fibrosis. Malignant and other transformed cells undergo apoptosis by suppression or activation of one or more genes such as bcl-2, c-myc, p53, TRPM-2, RP-2, RP-8, raf, abl, APO-11FAS, ced-3, ced-4, ced-9, etc. Drugs (methotrexate, cisplatin, colchicine, etc.), hormones (glucocorticoids), cytokines (tumor necrosis factor-alpha), radiation (free radicals) and hyperthermia can all initiate apoptosis. Increasing the temperature or duration of heating, or both, leads to cell death via necrosis. This physical process of indiscriminate cell killing is associated with inflammation and causes significant injury to normal, healthy cells.
For purposes of systemic hyperthermia, apoptosis of target cells is the therapy of choice. In the clinical setting it must be controlled under conditions of moderate heating so as to selectively differentiate and eliminate target cells with minimum toxicity to normal cells. Such controlled conductive heating by external technologies is inherently not possible. The thermal physical and thermophysiologic properties of cells vary and are dependent on their thermal conductivity, specific heat, density and blood perfusion among the various organs and tissues. Based on these properties, the actual temperatures at some of these sites are often ‘partitioned’, independent of one another and do not represent the monitored, mean “core” temperature achieved during therapy. Additionally, it is well recognized that it is the actual intracellular temperature increase, with it's associated internal physical and chemical changes, that is critical to the successful use of hyperthermia in exploiting the fundamental biochemical differences between normal and heat susceptible cells. Unfortunately, the initial cellular targets of all extracorporeal heating methods are the cell membrane and it's integrated proteins. The cell's internal contents, including mitochondria, compartmentalized enzymes, other organelles and any intracellular pathogens, etc., are progressively heated in sequence by thermal conduction from the outside-in. Thus, to sufficiently heat the interior of the cell, the external temperature must overcome the cellular and mitochondrial membranes, each composed of a lipid bilayer that acts as an effective thermal barrier.
By necessity, therefore, prior art heating methods require high external temperatures to establish a sufficient gradient to overcome the nonisotropic and non-homogeneous conductive heat loss between internal tissues and the insulating barrier of the cellular and mitochondrial membranes. For example, the Organetics PSI® (perfusion system (now First Circle Medical Inc.) device has to heat blood externally to 480 C (118.40 F) before returning it directly into the vascular system of the patient. Other extracorporeal circuit perfusion devices need to achieve ex vivo temperatures of 490 C (120.20 F.). Animal studies require temperatures of 540 (129.10 F) during the induction phase to achieve adequate target tissue temperatures. Safety in such prior art is therefore limited by the incipient destruction of surrounding tissues at the sites of the high temperature phases of heating. When lesser temperatures are attempted, effectiveness is compromised by either inadequate temperatures or duration of beating or development of thermotolerance. As a result, only regional hyperthermia has been widely used clinically and only in combination with more traditional techniques such as radiation and chemotherapy. Presently, none of the known heating technologies provide clinically safe and effective hyperthermia to treat systemic or disseminated disease. In order for systemic hyperthermia to become more widely used clinically, current heating methods must also overcome the use of labor intensive, complex equipment including invasive extracorporeal infusion and it's related toxicity problems to interposed tissues. Further, new hyperthermic technology must be compatible with noninvasive, real time thermometry.
The present invention avoids the problems of heat toxicity, inadequate target tissue heating, excessive cost, surgery, anesthesia and incompatibility with noninvasive temperature measuring devices: problems that are inherent to all therapeutic methods that deliver heat extracellularly, from the outside-in. This invention is an intracellular, therefore, an intracorporeal heating system which has additional distinct advantages. First, the human body is biochemically and physiologically designed to tolerate higher temperatures when heated from the inside-out as opposed from the outside-in. By example, in comparison to extracorporeal heating, which can safely generate a maximum body core temperature of 42° C. (107.6° F.), intracorporeal hyperthermia caused by strenuous exercise induces physiologic temperatures of up to 45° C. (113.0° F.) in muscle and liver with body core temperatures of up to 44° C. (111.2° F.). Exertional heat stroke patients have survived rectal body temperatures as high as 46.5° C. (115.2° F.) without any permanent clinical sequela. While the critical maximum temperature humans can tolerate is unknown, physiologic hyperthermic temperature induced under controlled conditions with adequate hydration have not shown any permanent untoward effects. Liver biopsies from subjects with such temperatures have not shown any significant microscopic abnormalities. Second, since heating with the present invention is chemically induced from within the cell, the actual intracellular therapeutic temperature will be higher than the measured core temperatures. As a result, intracellular organelles, including mitochondria, are heated at higher temperatures, undergo greater uncoupling and generate an increased flux of reactive oxygen species. Since oxygen free radicals, including superoxide, enhance and probably mediate the effects of hyperthermia, an improved therapeutic gain will be obtained at lower body core temperatures. Further, it is known that for each 0.5 degree Celsius increase in body temperature the metabolic rate and oxygen consumption increase 7%. Such an increase will assist heating the body in itself. Third, safety and control of temperatures with the present invention is far superior to that of exogenous methods. The body is naturally designed to dissipate heat from the inside-out. This is evident from the fact that a temperature gradient of 3.5°-4.5° C. exists between the visceral core and the skin. This gradient represents the transfer of heat from regions of high temperature to regions of low temperature, with ultimate heat loss from the skin to the environment through conduction, convection, radiation and sweat induced evaporation. The margin of safety and control represented by the ‘feedback gain’ of this intact physiologic heat dissipating system is extremely high, approximating 27-33. This rate of cooling can balance an influx of heat in a naked human body in a dry room at about 120° C. (248.0° F.). Thus, the human heat flow system permits the body to rid itself of excess endogenous heat very quickly and effectively. As a result, there is a wide margin of safety in case the target temperature is exceeded. In contrast, exogenous heating contravenes the natural physiologic flow of heat and its dissipating mechanisms. The natural heat dissipating mechanisms are overwhelmed and compromised. Control and safety over hyperthermia induced by extracellular means is thus fragile, with little room for error.